17alpha, 21-substituted methylenedioxy steroids and methods therefor



United States Patent 3,147,249 17a,21-SUBSTITUTED METHYLENEDIOXY STEROIDS AND METHODS THEREFOR Alberto Ercoli and Rinaldo Gardi, Milan, Italy, assignors to Francesco Vismara S.p.A., Casatenovo (Como), Italy, a corporation of Italy No Drawing. Filed June 11, 1962, Ser. No. 201,295 Claims priority, application Italy June 13, 1961 15 Claims. (Cl. 260-23955) 21 CH20\ 20 CO C where R is a member selected from the group consisting of aliphatic hydrocarbon radicals containing from 1 to 9 carbon atoms, cycloaliphatic hydrocarbon radicals of from 4 to 6 carbon atoms, arylaliphatic hydrocarbon radicals of 7 and '8 carbon atoms, phenyl, a fi-carboxyethyl group, a fi-carbomethoXy-ethyl group and a B-carboethoxy-ethyl group and R represents a lower alkyl radical of from 1 to 3 carbon atoms.

Preferred compounds of this invention are those in which R represents an aliphatic hydrocarbon radical of from 1 to 6 carbon atoms and particularly preferred are the l7a,21-(1-lower alkoxy)-pentylidenedioxy derivatives.

In the compounds of this invention the cyclopentanopolyhydrophenanthrene nucleus which is not shown in the above formula is generally substituted at the 3-position with an oxygenated function, such as a ketonic oxygen or a hydroxy group. If a hydroxy group is present it may be protected in the form of an ether group containing a lower alkyl radical of from 1 to 3 carbon atoms or in the form of an ester group containing a lower alkanoyl radical, of from 1 to 3 carbon atoms or a benzoyl radical. Other substituents, such as hydroxy, keto, halogen, ether and methyl groups, may be also contained at other positions of the cyclopentanopolyhydrophenanthrene nucleus, as for instance at positions 1, 2, 4, 6, 7, 9, 11, 16. The steroid may be completely saturated or have one or more double bonds, as for instance in the 1:2, 3:4, 4:5, :6 and/or 9:11 positions of the molecule.

Preferred 17:1,21- l'-alkoxy)-1'-substituted methylenedioxy steroids are those containing a double bond in the 4:5 or 1:2 and 4:5 positions, a keto group at the 3-position, a keto group or a hydroxy group at the 11 position and, coupled with the llfi-hydroxy group a halogen, particularly fluorine, at the 9-position. Other substituents may occur at 6 or 16 positions.

These compounds may be represented by the following structural formula:

where R and R are as defined above, X represents ketonic oxygen or a hydroxy group fi-oriented, Y is hydrogen or fluorine, W is hydrogen, fluorine or methyl and R is hydrogen, an uor fi-methyl group or an a-hydroxy group, and 1:2 unsaturated derivatives thereof.

The new 17u,21-(1'-alko);y)-1-substituted methylenedioxy derivatives of this invention are obtained by treating a l7a,21-dihydroxy-20-keto steroid with an orthoester of the formula:

in which R and R are as defined above, in the presence of an acid catalyst and in solution in an appropriate organic solvent. Preferred solvents are dimethylformamide, benzene, hexane, isooctane or halogenated solvents, such as chloroform and carbon tetrachloride. The acid catalysts of the reaction may be selected from sulfonic aromatic acids, for instance, toluen-, benzen-, or naphthalensulfonic acid, Lewis acids, such as SnCl or SbCl and salts of organic bases with mineral acids, particularly pyridine hydrochloride.

The orthoester employed for the reaction is preferably a methylor ethylester of an orthocarboxylic acid. Exemplary of these ortho-acids are: ortho-acetic, orthopropionic, ortho-butyric, ortho-isobutyric, ortho-valeric, ortho-iso-valeric, ortho-caproic, ortho-oenanthic, orthocaprylic, ortho-pelargonic, ortho-capric, ortho-cyclobutanoic, ortho-cyclopentanoic, ortho-hexahydrobenzoic, ortho-benzoic, ortho-fiphenylpropionic, ortho-B-carbomethoxypropionic and ortho-B-carboethoxypropionic.

These compounds are generally well known in the literature. They can be easily prepared according to the Pinner method (Ber. 16, 1643; 1883) by treating a nitrile of formula R-CN, where R is as defined above, with an alcohol of the formula R OH, where R is as defined above, and preperably with methanol or ethanol, by passing through the corresponding imido ether hydrochloride. The :,21-dihydroxy-ZO-ketosteroid, starting material, may be completely saturated or have one or more double bonds as indicated above. It may contain functional groups at the various positions of the cyclopentanopolyhydrophenanthrene nucleus and specifically the substituents mentioned above. However it is preferred to exclude from the reaction with the desired orthoester a 17a,21-dihydroxy-20-ketosteroid containing a free hydroxy group at the 16-position. Other substituents at the 16-position or free hydroxy groups at other positions of the steroid nucleus do not interfere with the process for converting a 17a,21-dihydroxy steroid to the corresponding 17a,21-( l-alkoxy) -1-substituted methylenedioxy derivative.

Exemplary of 17a,21-dihydroxy-ZO-ketosteroids starting material are:

4-pregnene-17tx,21-diol-3,20-dione 4-pregnene-11;3,17a,21-triol-3 ,ZO-dione 4-pregnene-17tx,21-dio1-3,20-dione 1,4-pregnadiene-1 1,8,17a,21-triol-3 ,ZO-dione 4,6-pregnadiene-17a,21-diol-3 ,11,20-trione 1-pregnene-17u,21-diol-3,11,20-trione 9a-fiuoro- 1,4-pregnadiene- 1 lo, 1711,21-t1'i0l-3 ,ZO-dione 4u-chloro-5u-pregnane-17a,21-diol-3,20-dione 4a-bromo-5a-pregnane-17a,21-diol-3,20-dione 16,6-bromo-4-pregnene-17a,21-diol-3 ,ZO-dione 16fi-bromo-4-pregnene-17a,21-diol-3,11,20-trione Sa-pregnane-B ,17a,21-triol-20-one 3 ,B-ethoxy-S ot-pregnane-17a,2 1-diol-20-one 5-pregnene-3fi,17a,2l-triol-20-one 3 -benzoate 5 a-pregnane- 17 a,21 -diol-3 ,11,20-trione Sa-pregnane-I118,17a,2l-triol-3,20-di0ne 4,9(11)-pregnadiene-17u,21-diol-3 ,ZO-dione 5a-pregnane-4ot,17a,21-triol-3 ,20-dione 3 4-pregnene-17a,21-dio1-3 ,11,20-trione 5a-pregnane-3a,17a,'21-triol-20-one 3-formate 5a-pregnane-3a,17a,21-triol-20-one 3-acetate 3-propoxy-5a-pregnane-170:,2 l-diol-ZO-one 6a-methyl-1,4-pregnadiene-1 118,17a,21-trio1-3,20-dione 6a-fluoro-1,4-pregnadiene-11p,17a,21-triol-3,20-dione 6a-methyl-4-pregnene-17a,21-diol-3 ,1 1,20-trione 6a-fluoro-4-pregnene-17a,21-diol-3, 1 1,20-trione 19-nor-4-pregnene-l1,8,17a,21-triol-3 ,ZO-dione 4-pregnene-6,17a,21-triol-3,20-dione 16,6-methyl-1,4-pregnadiene-11B,17a,2l-triol-3 ,20-dione 9a fluoro 16B methyl 1,4 pregnadiene 1l[3,17a,21

triol-3,20-dione 9a fluoro 1,4 pregnadiene 1l}3,l6oz,l7a,2l tetrol- 3,20-dione 16-acetate 9a fluoro 16/3 methyl 1,4 pregnadiene 115,160, 2a-methyl-4-pregnene-1 711,2 1-diol-3, 1 1 ,20-trione.

The reaction of a 1711,2l-dihydroxy-20-ketosteroid with the desired orthoester may be carried out at a temperature from about 60 C. to about 130 0., preferably between 75 and 115 C., for a period of from minutes to 4 hours. The most satisfactory yields of l7a,21-(1-alkoxy)-1'-substituted rnethylenedioxy steroids are realized by carrying out the reaction in an apparatus equipped with a descending condenser. A portion of the solvent is distilled off and the remaining solution is neutralized by addition of a few drops of pyridine. The 17a,21-(1-alkoxy)-1'-substituted rnethylenedioxy steroids are then obtained by concentration of the reaction mixture to dryness in vacuo followed by recrystallization of the product in the usual manner.

If the resulting steroid derivative contains a bromine atom in the 16-position, it can be submitted, if desired, to a further step in order to replace the bromine atom with a hydroxy group. This is readily accomplished by treating the 17a,21-(1-alkoxy)-1'-substituted methylene-dioxy-16 S-brorno steroid with silver acetate in the presence of sodium acetate according to known procedures (see, for example, I. Am. Chem. Soc. 82, 504; 1960), thus obtaining the corresponding 17a,21-(l'-alkoxy)-1'-substituted methylenedioxy-lGfi-acetoxy derivative.

Since the new compounds of this invention are stable under basic conditions, they can be submitted, if desired, to alkaline treatments in order to convert by hydrolysis the esterified hydroxy groups present in the steroid nucleus to free hydroxy groups. Thus, for example, the above mentioned 17a,21-(1'-alkoxy)-1-substituted methyIenedioxy-lGfi-acetoxy steroid is reacted with potassium carbonate to give, by simultaneous hydrolysis and epimerization at the 16-position, the corresponding 17x,21-(1'-a1koxy)-1-substituted methylenedioxy-16a-hydroxy derivative.

Similarly a 17a,21-(1-alkoxy)-l-substituted methylenedioxy-16a-hydroxy steroid, such as for instance, 17a, 21 (1 methoxy) pentylidenedioxy 90c fiuoro 1,4- pregnadiene-11fi,16a-diol-3,20-dione, can be obtained by alkaline hydrolysis of the corresponding 16a-acetoxy derivative. The 16a-acetoxy-17a,2l-dihydroxy steroid, starting material for the reaction with a lower alkyl ester of the desired orthocarboxylic acid, may be obtained in turn by acetylating with acetic anhydride in pyridine the l6a,l7a,2l-trihydroxy steroid-21-hemisuccinate and selectively hydrolyzing the 16a-acetate-2l-hemisuccinate thus obtained with magnesium hydroxide according to a method described by us in Gazz. Chim. Ital. 89, 1382; 1959.

The new 17a,21-(1'-alkoxy)-1-substituted methylenedioxy steroids of this invention, being stable under basic conditions, could be employed for the same purposes as the corresponding 17a,21-(1'-alkoxy)-methylenedioxy derivatives, disclosed in our copending application Serial No. 201,296, filed on June 11, 1962, that is to afford protection for the dihydroxy-acetone side chain when it is desired that certain reactions, such as a Claisen condensation, be performed on the steroid nucleus without modification of the dihydroxy-acetone moiety. However, while the 17 a,

21-(1'-alkoxy)-methylenedioxy derivatives can be easily cleaved by short treatment with a mineral acid in hot methanol to re-establish the dihydroxy-acetone side chain, the new 17 a,21-(1-alkoxy)-l-substituted rnethylenedioxy derivatives of this invention cannot regenerate the free dihydroxyacetone function, even under strong acid conditions. We have found that the new 17a,21-(1-a1koxy)- 1-substituted methylenedioxy steroids are quantitatively converted by treatment with mineral acids, even concentrated, to the corresponding new 17a-mon0esters of 17 a,- 2l-dihydroxy steroids. Therefore the new compounds of this invention are particularly useful for the preparation of the 17a-monoesters. This process of hydrolyzing the l7a,21-(1'-alkoxy)-1'-substituted rnethylenedioxy derivatives to obtain a selective esterification of the 17a-hydroxy group of a 17a,21-dioxy steroid is more fully described in our copending application Serial No. 201,297, filed on June 11, 1962.

In addition to their utility as intermediates for the preparation of the 17x-monoesters, the 17a,21-(1'-a1koxy)-1- substituted rnethylenedioxy steroids represented by the Formula II above are also useful for their remarkable anti-inflammatory properties. In particular, the 1711,21- cyclic orthoesters of cortisone, cortisol, prednisone and prednisolone in which the 1-substituent is an alkyl group of from 1 to 6 carbon atoms, exhibit an anti-inflammatory activity several times higher than the parent hormones. For instance, 17a,21-(1'methoxy)-pentylidenedioxy-1,4- pregnadiene-l1fl-ol-3,20-dione has been found to be at least seventy times more effective than prednisolone itself. These compounds can be used in the treatment of rheumatic and cutaneous diseases.

The following examples are illustrative of the products and methods of this invention, but are not to be construed as limiting.

Example 1 A mixture of 2 g. of 4-pregnene-17m,21-diol-3,20-dione (Compound S), 4 mg. of p-toluensulfonic acid and 800 cc. of benzene is introduced into a flask equipped with a descending condenser and distilled for a few minutes to remove any possible trace of moisture.

To the resulting mixture there are added dropwise 1.5 cc. of methyl orthoacetate (prepared as described by P. P. T. Sah., J.A.C.S. 50, 516; 1928). The distillation is continued until the volume is reduced to 250 cc. whereupon a few drops of pyridine are added to neutralize the p-toluensulfonic acid The solution is evaporated to dryness under vacuum and the residue on crystallization from methanol consists of l7a,21-(1'-methoxy)-ethylidenedioxy-4-pregnene-3,ZO-dione, M. Pt. 176-178 C.; ]D=+91.5 (dioxan).

Example 2 1.5 g. of 4-pregnene-17a,21-diol-3,20-dione (Compound S) are suspended in 1.5 cc. of dimethylformamide with 4 mg. of p-toluensulfonic acid. Then 1.5 cc. of methyl orthovalerate (prepared as described by Brooker and White, J.A.C.S. 57, 2480; 1935), are added dropwise to the mixture which is heated to C. for approximately 30 minutes. A few drops of pyridine are added and the solvent is evaporated in vacuo. The solid residue is taken up with ethanol, filtered and recrystallized from ethanol to obtain 17oz,21-( l'-methoxy -pentylidenedioxy-4-pregnene-3,20-dione, M. Pt. 136139 C.; [a];;,: +72 (dioxan).

Example 3 2.5 g. of 4-pregnene-17u,2l-diol-3,20-dione and 5 mg. of benzensulfonic acid are suspended in 900 cc. of benzene. The resulting mixture is heated and distilled for a few minutes, then it is treated with 2 cc. of methylorthocaproate (prepared as described by Brooker and White, I.A.C.S. 57, 2480; 1935). Following the procedure described in Example 1, 17a,21-(1'-meth0xy)- hexylidenedioxy-4-pregnene-3,ZO-dione is obtained, M, Pt. 129131 C.; [a] =+7l.5 (dioxan). In the same manner as above, by substituting of methyl ortho [fl-carbomethoxy-propionate (prepared as described by Mo- Elvain and Schroeder, J.A.C.S 71, 40; 1949), for methyl orthocaproate, 170:,21 (1' methoxy-3'-carbomethoxy)- propylidenedioxy-4-pregnene-3,20-dione is prepared, melting point: 145-147 C.; [a] =+7O (dioxan).

Example 4 A suspension of 2 g. of 17a,21-(1'-methoxy-3'-carbomethoxy) propylidenedioxy-4-pregnene-3,20-dione (obtained as described in Example 3) in 100 cc. of methanol and 14 cc. of a solution of potassium carbonate are heated to reflux on a water-bath for 3 hours. Most of the solvent is eliminated under vacuum, then the mixture is taken up with water and 6 cc. of 10% acetic acid are added to neutralize the excess of potassium carbonate. The solution is poured onto ice, treated with 10 cc. of 10% hydrochloric acid and extracted with methylene chloride.

By evaporating the solvent, an oily residue is obtained which, taken up with methanol, yields 17a,21-(1'-methoxy 3' carboxy) propylidenedioxy 4-pregnene-3,20- dione.

Example 5 Following the same procedure as in Example 1 and substituting 4-pregnene-l7a,21-diol-3,20-dione by 4,9 1 1 pregnadiene 17 a,21-diol-3,20-dione, the corresponding 170:,21 (1' methoxy)-ethyl-idenedioxy-4,9(11)-pregnadiene-3,20-dione is obtained, M. Pt. 176-1775 C; [m] =+65.5 (dioxan).

Example 6 To 1000 cc. of anhydrous toluene, 3 g. of 4-pregnene- 17a,21-diol-3,11,20-trione (cortisone) and 5 mg. of sulphosalicylic acid are added. The resulting mixture is distilled for a few minutes and treated, drop by drop, with 2 cc. of methyl orthoacetate. The distillation is continued until the volume is reduced to about 250 cc. The resulting solution is then neutralized with pyridine and evaporated in vacuo to a residue which, taken up with methanol, yields a solid which is recrystallized from methanolmethylene chloride to. give 17a,21-(1-methoxy)-ethylidenedioxy-4-pregnene-3,11,20-trione, M. Pt. 210-214; [a] =-|150 (dioxan).

Example 7 2 g. of 4-pregnene-17a,21-diol-3,l1,20-trione (cortisone) are suspended in 800 cc. of benzene with 4 mg. of pyridine hydrochloride. The mixture is distilled for a few minutes and then treated with 1.5 cc. of methyl orthovalerate. The distillation is continued and the volume reduced to 200 cc. After addition of a few drops of pyridine, the solvent is evaporated in vacuo. The residue on crystallization from methanol consists of 17u,21-(1'-methoxy)- pentylidenedioxy 4 pregnene-3,l1,20-trione melting at 163165 C.; [a] =|126 (dioxan).

Similarly, by substituting methyl-orthocaproate (prepared as described by Brooker and White, J.A.C.S. 57, 2480; 1935), for methyl orthovalerate, l7ot,21-(1-rnethoxy -hexylidenedioxy-4-pregnene-3 ,1 1,20-trione at 119-120 C.; [a] =+l23 (dioxan) is prepared.

Example 8 To a suspension of 1 g. of 4-pregnene-11;8,17a,21-triol- 3,20dione (cortisol) in 500 cc. of benzene are added 2 mg. of p-toluensulfonic acid. The resulting reaction mixture is distilled in order to remove any trace of moisture and 1 cc. of methyl orthoacetate is added. After distillation in vacuo a solid separates which by recrystallization from ethanol gives 17a,21-(l'-methoxy)-ethylidenedioxy- 4 pregnene 11p ol 3,20-dione, M. Pt. 222224 C.; [a] ':+116 (dioxan).

Example 9 To 1.5 g. of 4-pregnene-11fi,17a,21-triol-3,20-dione (cortisol) dissolved in 600 cc. of anhydrous benzene, 4

melting 7 mg. of naphthalene sulfonic acid are added. The mixture is distilled for a few minutes and reacted with 1.5 cc. of methyl orthovalerate. The heating is continued until the volume of the solution is reduced to cc. The naphthalenesulfonic acid is neutralized with a few drops of pyridine and the liquid evaporated in vacuo. The residue taken up with methanol-methylene chloride yields 17a,2l (1 methoxy) pentylidenedioxy 4 pregnene- 11fl-ol-3,20-dione, M. Pt. 184-186 C.; [a] =+101 (dioxan).

A similar reaction carried out with propyl orthovalerate yields 17:1,2 1 1'-propoxy) -pentylidenedioxy-4-pregnene- 11[3-0l-3,20-di0ne melting at 200205 C.; [u] =+102 (dioxan).

Example 10 A mixture of 3 g. of l,4-pregnadiene-l7a,2l-di0l-3,11, 20-trione (prednisone), 5 mg. of p-toluenesulfonic acid and 3 cc. of dimethylformamide is reacted with 4 cc. of methyl orthoacetate. The resulting mixture is treated following the same procedure as in Example 2 to prepare 17u,21-(1'-methoxy)-ethylidene-1,4-pregnadiene-3, 11,20-trione, M. Pt. 226228 -C.; [a] =+138 (dioxan).

Similarly, 171:,21-(1-ethoxy)-ethylidenedioxy-1,4-pregnadiene-3,1l,20-trione, melting at 192194 C; [a] +132 (dioxan) is obtained.

Example 11 1.2 g. of 1,4-pregnadiene-17a,21-diol-3,11,20-trione (prednisone) in 500 cc. of toluene are mixed with 3 mg. of sulphosalicylic acid. The mixture is distilled, 1 cc. of methyl orthovalerate is added and the volume reduced to 100 cc. Then a few drops of triethylamine are added to neutralize the sulphosalicylic acid and the solvent eliminated in vacuo. The residue crystallized from methanol yields 17a,21-( 1-methoxy)-pentylidenedioxy-1,4- pregnadiene-3,11,20-trione, M. Pt. ZOO-203 C.; [a] +114 (dioxan).

In the same manner as above, but employing methyl ortho fl-carbomethoxy-propionate instead of methyl orthovalerate, 17m,21-( 1-methoxy-3'-carbomethoxy) -propylidenedioxy-1,4-pregnadiene-3,11,20-trione is prepared. The latter compound, dissolved in methanol, is hydrolised following the procedure described in Example 4, to obtain :,21 (1 methoxy 3 carboxy) propylidenedioxyl,4-pregnadiene-3,11,20-trione.

Example 12 To a moisture-free solution of 4 g. of 1,4-pregnadiene- 11e,17a,21-tri0l-3,20 dione (prednisolone) in 1200 cc. of benzene, there is added 5 mg. of p-toluenesulfonic acid and 3 cc. of methyl orthoacetate. The mixture is distilled to reduce the volume to 300 cc., and, after addition of pyridine, the liquid is completely evaporated under vacuum to obtain a solid residue. Upon crystallization from methylene-methylene chloride there is obtained 17,21- (1' methoxy) ethylidenedioxy 1,4 pregnadiene-llfiol-3,20-di0ne, M. Pt. 191-193" C.; [111 +83 (dioxan).

Similarly, 17 a,21 (1-methoxy)-pentylidenedioxy-1,4- pregnadiene-l1B-ol-3,20 dione, M. Pt. 157159 C.; [a] =|64 (dioxan) and l7a,21-(1-methoxy)-hexylidenedioxy-1,4-pregnadiene-11,B-ol-3,20-dione, M. Pt. 137- 141 C.; [oc] =+6Z (dioxan) are prepared.

Example 13 A solution of 1.5 g. of 1,4-pregnadiene-11fi,17 x,21-triol- 3,20-dione and 4 mg. of pyridine hydrochloride in 600 cc. of carbon tetrachloride is distilled to remove any trace of moisture. The resulting mixture is treated with 1.5 cc. of methyl ortho-oenanthate, Kp 192 C. (prepared following the method described by Pinner Ber. 16, 1643; 1883). Following the same procedure as in 7 Example 12, 17a,21-(1'-methoxy)-heptylidenedioxy-1,4- pregnadiene-l1fl-o1-3,20-dione melting at 148151 C. [u] =+62 (dioxan) is obtained.

Similarly, 9 a-fiuoro- 17 ;,21- 1'-methoxy) -ethylidenedi oxy-1,4-pregnadiene-1lfi-ol-3,20-dione, M. Pt. 220-222 C.; [a] =+78 (dioxan), and 9a fiuoro 1711,21 (1 methoxy) pentylidenedioxy-1,4-pregnadiene 11B 01-3, 20-dione, M. Pt. 213215 C.; [a] =+63 (dioxan) are prepared Example 14 By treating 1.5 g. of 9a-chloro-1,4-pregnadiene-l15,1711, 21-triol3,20-dione, with 1.2 cc. of methyl ortho-fl-phenylpropionate under the same conditions as described in Example 13,9a-chloro-17a,21-( 1-methoxy) -;8-phenyl-propylidenedioxy 11p ol-1,4-pregnadiene-3,20-dione is obtained.

Similarly, 9a bromo-l7u,21-(1'-methoxy)-hexahydrobenzylidenedioxy 11 p ol 1,4-pregnadiene-3,20-dione is prepared.

Example 15 Reacting 6 g. of 1,4-pregnadiene-11fi,17a,21-triol-3,20'- dione and 8 mg. of =benzensulphonic acid, dissolved in 1500 cc. of benzene, with 4.5 cc. of methyl ortho-B-carbomethoxy-propionate and following the same procedure as in Example 1, 17a,21-(1'-methoxy-3'-carbomethoxy)- propylidenedioxy-1,4-pregnadiene-11}3-ol-3,20-dione is isolated, M. Pt. 153156 C.; [a] =+6l (dioxan).

By submitting this compound to hydrolysis as described in Example 4, 17a,21-(1'-methoxy-3'-carboxy)-propylidenedioxy-1,4-pregnadiene-11fl-ol-3,20-dione, melting at 160-162 C.; [a] =+57 (dioxan), is obtained.

Example 16 Into a solution of 0.5 g. of Sa-dihydrocortisone and tin tetrachloride in 200 cc. of benzene, previously distilled in order to remove any possible trace of moisture, there is added dropwise 1 cc. of methyl ortho-acetate. The resulting mixture is treated as described in Example 1 and the solid residue obtained on crystallization from ethanol consists of 17a,21-(1-methoxy)-ethylidenedioxya-pregnane-3,11,20-trione, M. Pt. 208212 C.; [a] +57 (dioxan).

Following the same procedure as above and substituting the Sa-dihydrocortisone by the 5a-dihydrocortisol, 17oz, 21 (1' methoxy) ethylidenedioxy 5o: pregnanc- 11fl-ol-3,20-dione melting at 218-221 C.; [a] =|51 (dioxan), is obtained.

Example 17 To 1.5 g. of 3fi-ethoxy-5a-pregnane-17a,21-di0l-20-one dissolved in 600 cc. of isooctane containing 4 mg. of p-toluensulfonic acid are added, after distillation, 1.5 cc. of methyl orthoacetate. The mixture is treated as described in Example 1 and a solid residue separates which on crystallization from ethanol gives 3j3-th0XY-17a,21 (1-methoxy)-ethylidenedioxy-5a-pregnane-20-one, M. Pt. 173-177 C.; [a] =+20.5 (dioxan).

Similarly, 1711,21 (1'-methoxy) ethylidenedioxy 5apregnane-3fi-ol-20-one 3-formate and 17a,21-(1'-rnethoxy)-ethylidenedioxy-5a-pregnane-3fl-ol-20 one 3 acetate are prepared.

Example 18 2 g. of 6a-methyl-1,4-pregnadiene-17a,21-diol3,11,20- trione suspended in 800 cc. of moisture-free carbon tetrachloride containing 4 mg. of SbCl are treated with 1.5 cc. of methyl orthocrotonate (prepared according to the Pinner method Ber. 16, 1643; 1883), and the solution is distilled. Then a few drops of pyridine are added and the solvent is evaporated in vacuo. The residue crystallized from methanol yields 6a-methyl-17a,21-(1'-methoxy)- crotylidenedioxy-1,4-pregnadiene3, 1 1,20-trione.

In the same manner 2a-methyl-17a,21-(1-methoxy)- butylidenedioxy-4-pregnenc 3,11,20 trione, l7a,2l (1'- ethoxy)-isobutylidenedioxy-1-pregnene-3,11,20-trione and 8 17a,21 (1 propoxy) decylidenedioxy 4,6 pregnadiene-3,11,20-trione are prepared.

Example 19 5 g. of 16fi-methyl-1,4-pregnadiene-11B,17a,21-triol- 3,20-dione in 1500 cc. of toluene are treated with 6 mg. of p-toluensulfonic acid and 4.5 cc. of ethyl orthopelargonate (prepared following the Pinner method Ber. 16, 1643; 1883). Following the procedure described in Example 1, 16B methyl 17a,21-( 1'-ethoxy)-nonylidenedioxy-1,4- pregnadiene-l1fi-ol-3,20-dione is obtained.

Similarly there is prepared l7a,2l( 1'-ethoxy-1-cyclopentyl)-methylenedioxy-4- pregnene-6B-ol-3,ZO dione;

16a-methyl-17u-21-( 1'-meth0xy-3-phenyl) -propylidenedioxy- 1 ,4-pregnadiene- 1lB-0l-3,20-dione;

4oc-Chl0l'0- 17a,21 1-ethoxy-benzylidenedioxy-Sa-pregnane-3,20-dione;

4a-bromo-17a,21-(1-propoxy)-iso-pentylidenedioxy-5apregnane-3 ,20-dione.

Example 20 The same procedure as described in Example '2 is carried out in order to obtain the following compounds:

17a,21-( 1'-methoxy)-crotylidenedioxy-Sa-pregnane-4aol-3,20-dione; 6ozfll10rO-17a,2l- 1-eth0xy) -hexylidenedioxy-1,4-pregnadiene-l1[3-0l-3,20-dione; Qa-fluoro-l65-methyl-17a,21-(1'-iso-propoxy)-octylidenedioxy-4-pregnene-3,l 1,20-trione; 17a,21-(1'-propoxy)-crotylidenedi0xy-4-pregnene-6fi-ol- 3 ,20-dione; 6B-methyl- :,2 l 1'-ethoxy) hexahydrobenzylidenedioxy-1,4-pregnadiene-11B-ol-3,20-dione; 9a-fluorol6p-methyl- 17a,21-( 1-iso-pr0poxy) -octylidenedioxy- 1 ,4-pregnadiene-1 1,8-01-3 ,20-dione; 9a-chloro-17a,21-(1-methoxy)-heptylidenedioxy-4-pregnene-l1fi-ol-3,20-dione; l9-1'10r17a,2l- 1'-ethoxy -ethylidenedioxy-4-pregnenel 118-ol-3,20-dione.

Example 21 2 g. of triamcinolone 21-hemisuccinate (J. Pharm. Sciences 50, 866; 1961), is treated with 0.5 cc. of acetic anhydride in 3 cc. of pyridine solution at room temperature to give 9a-fluoro-1,4-pregnadiene-11,8,16a,17a, 21-tetraol-3,20-dione l6-acetate 21-hemisuccinate. The product (1.5 g.) is reacted with magnesium hydroxide in disodium phosphate solution and the resulting triam cinolone l6-monoacetate is treated with methyl orthovalerate as in Example 2 to give l7a,21-(1-rnethoxy)- pentylidenedioxy 9a fiuoro 1,4 pregnadiene-11B,16adiol-3,20-dione 16-acetate. Hydrolysis of this latter by heating with potassium carbonate in dilute methanol solution provides 17 (1,2 1 1'-methoxy) -pentylidenedioxy-9afiuoro-1,4-pregnadiene-11fl,16ot-diol-3,20-dione.

Example 22 1 g. of 16fl-bromo-4-pregnene-17a,21-diol-3,20-dione, prepared by acid hydrolysis from the corresponding 21- acetate (obtained in turn as described in J. Am. Chem. Soc. 72, 5145; 1950), is treated with methyl orthoacetate as in Example 1 to give 17a,21-(1'-methoxy)-ethylidenedioxy-l6;3-bromo-4-pregnene-3,20-dione. This compound (0.6 g.) is dissolved in 20 cc. of dimethylformamide and the solution heated to reflux for two hours with an excess of silver acetate in the presence of sodium acetate to form 17oz,21-( 1-methoxy)-ethylidenedioxy-16B-acetoxy-4-pregnene-3,20-dione. This latter by treatment with potassium carbonate in 50 cc. of methanol solution, according to the method described in J. Am. Chem. Soc. 81, 1256; 1959, gives the 17a,21-(l'-methoxy)-ethylidenedioxy-l6ahydroxy-4-pregnene-3,20-dione.

In the same manner the corresponding derivative of 16a-hydroxy cortisone is prepared.

9 We claim: 1. A compound selected from the group consisting of a steroid compound of the formula:

where R is a member selected from the group consisting of aliphatic hydrocarbon radicals of from 1 to 9 carbon atoms, cycloaliphatic hydrocarbon radicals of from 4 to 6 carbon atoms, arylaliphatic hydrocarbon radicals of at least 7 and no more than 8 carbon atoms, phenyl, li-carboxyethyl, fl-carbomethoxyethyl and B-carbethoxyethyl, R is lower alkyl of from 1 to 3 carbon atoms, R is a member selected from the group consisting of hydrogen, a-methyl, B-methyl and u-hydroxy, X is selected from the group consisting of hydrogen, ketonic oxygen and fil-hydroxy, Y is selected from the group consisting of hydrogen, fiuoro, chloro and bromo, and W is selected from the group consisting of hydrogen, halogen, methyl and hydroxy; and A -dchydro derivatives of said steroid compound.

2. A compound of the formula:

of aliphatic hydrocarbon radicals of from 1 to 9 carbon atoms, cycloaliphatic hydrocarbon radicals of from 4 to 6 carbon atoms, arylaliphatic hydrocarbon radicals of at least 7 and no more than 8 carbon atoms, phenyl, B-carboxyethyl, fi-carbomethoxyethyl and p-carbethoxyethyl, R is lower alkyl of from 1 to 3 carbon atoms, R is a member selected from the group consisting of oxygen, a-hydroxy, fl-hydroxy, lower alkoxy of from 1 to 3 carbon atoms, lower alkanoyloxy of from 1 to 3 carbon atoms and benzoyloxy, R is selected from the group consisting of hydrogen, chloro, bromo and hydroxy and X is selected from the group consisting of hydrogen, ketonic oxygen and p-hydroxy.

3. 170;,21 (1 methoxy) ethylidenedioxy 4,9(l1)- pregnadiene-3,20-dione.

4. 17a,21 (1' ethoxy) isobutylidenedioxy 1 pregnene-3,11,20-trione.

5. 1701,21 (1' propoxy) decylidenedioxy 4,6 pregnadiene-3,1 1,20-trione.

6. 19 nor 170:,21 (1' ethoxy) ethylidenedioxy- 4-pregnene-l lfi-ol-3,20-dione.

7. 17,21 (1' methoxy) pentylidenedioxy 9a filloro-1,4-pregnadiene-l lfi,16nc-diOl-3,20-dl0ll6.

8. 17a,21 (1 methoxy) ethylidenedioxy 4 pregnene-3,20-dione.

9. 17a,21 (1 methoxy) n pentylidenedioxy 4- pregnene-l 1,6-ol-3,20-dione.

10. 17oz,21 (1' methoxy) ethylidenedioxy 1,4- pregnadiene-l 1 3-01-3 ,20-dione.

11. 17a,21 (1' methoxy) n pentylidenedioxy 1,4- pregnadiene-l1 3-ol-3,20-dione.

12. l7a,-21 (1' methoxy) n hexylidenedioxy 1,4- pregnadiene-l 1;8-ol-3,20-dione.

l3. 170:,21 (1 methoxy 3 carboxy) propylidenedioXy-1,4-pregnadiene-1 lfi-ol-S ,20-dione.

14. 1701,21 (1' methoxy) n pentylidenedioxy 9afluoro-1,4-pregnadiene-11/3-ol-3,20-dione.

15. 170:,21 (1 methoxy) n pentylidenedioxy 1,4- pregn adiene-3, 1 1,20-trione.

References Cited in the file of this patent Smith et al.: J.A.C.S., S2, 1960, PP. 4625-4629. Tanabe et al.: J.A.C.S., 83, February 5, 1961, pp. 756 and 757.

- U ITED STATES PATENT OIFFICE CERT'L ICAZIE OF GORRECTION Patent No. 3,147,249, September 1, 1964 Alberto Ercoli et a1.

' It is hereby certified that error appears in the above numbered pateht requiring correction and that the said- Letters Patents ho'ul d read as corrected below.

Column 2,- line 36', for "prepenably" read preferab-l dion'e "collimn' '6 line 22, for "l7,2l-( l m-ethoxy) ethylidene" read 1%,21-(1 methoxy)ethylide nedioxy column 8, line 17, for "(l eth0xy" read l"-eth,oxy)

Signed and sealed this 4th day 0f'Mayll965.

" (SEAL) Attest:

ERNEST w. SWIDER EDWARD J, BRENNER Aitgzsting Officer Commissioner of Patents. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A STEROID COMPOUND OF THE FORMULA: 